This application addresses the broad Challenge Area Enabling Technologies and the primary specific Challenge Topic 06-EB-103 Development of Non-Invasive Therapies and Treatment Procedures (a secondary specific Challenge Topic is 06-EB-102* Development of Biomedical Technologies and Systems). Patients with advanced head and neck squamous cell carcinomas (HNSCC) continue to represent a challenging disease category which faces a poor prognosis and often suffers poor cosmesis from currently conventional treatment practices. Although adjuvant radiochemotherapy has been shown to improve overall survival, innovative therapeutic approaches are clearly needed in view of these persistently poor outcomes. Thermal ablation is a therapeutic modality that has gained acceptance in the treatment of some advanced cancers. We propose incorporation of thermal ablation into the treatment of advanced superficial HNSCC recurrences and/or positive neck lymph nodes. We contend that non-invasive thermal ablation may circumvent or reduce the need for surgery and augment ionizing radiation therapy;thus, possibly providing significant outcome improvements in this high-risk patient population. However, commercially available thermal therapy technologies were not designed for application in the head and neck, and those most accepted, like radiofrequency ablation, are relatively invasive and poorly suited. Therefore, we propose to develop a new technology optimized for thermal ablation of superficial HNSCC and/or positive lymph nodes, namely, the SonoKnife, a scanned, line-focused ultrasound thermal therapy system specifically designed for non-invasive thermal ablation (target temperatures of 50-60[unreadable]C). Our working hypothesis is that non- invasive, scanned, line-focused ultrasound can replace/augment surgery in the treatment of advanced superficial HNSCC and/or positive neck nodes. To test this hypothesis we will pursue the following specific aims: (1) Develop a scanned, line-focused, high power ultrasound thermal therapy system (a SonoKnife) to deliver controlled thermal ablation (50-60[unreadable]C) to superficial malignant lesions non-invasively. In this project we will develop applicators specifically for superficial head and neck lesions and neck lymph nodes. (2) Implement a practical and clinically useful thermoradiotherapy treatment planning system (TTPS). Three- dimensional, image-based, ultrasound and thermal models will be developed to build the TTPS for the SonoKnife. A computational interface will be developed to communicate with radiotherapy treatment planning systems to integrate thermal and radiation dose data analysis. And (3) perform in vivo studies to evaluate the SonoKnife (SA1) and the TTPS (SA2) in clinically-relevant situations. PUBLIC HEALTH RELEVANCE: Our long-term goal seeks to maximize the therapeutic benefits of thermoradiotherapy by developing specialized heating systems. In particular, we seek to a) improve thermal doses to maximize direct thermal cytotoxicity, and b) deliver ionizing radiation with thermal therapy to maximize heat-induced radiosensitization. We propose the development of a new non-invasive thermal ablation technology to replace or reduce the need for surgery in patients with advanced superficial cancer in the head, neck or neck lymph nodes. We called this new technology the SonoKnife, a scanned, line-focused ultrasound thermal therapy system specifically designed for non-invasive thermal ablation.